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The Journal of Neuroscience, April 1, 2003, 23(7):2517
BRIEF COMMUNICATION
Tumor Necrosis Factor- Induces Mechanical Allodynia after
Spinal Nerve Ligation by Activation of p38 MAPK in Primary Sensory
Neurons
Maria
Schäfers1, 3,
Camilla I.
Svensson1, 2,
Claudia
Sommer3, and
Linda
S.
Sorkin1
1 Anesthesiology Research Laboratory and
2 Department of Pathology, University of California San
Diego, La Jolla, California 92093-0818, and 3 Department of
Neurology, University of Würzburg, 97080 Würzburg, Germany
Tumor necrosis factor- (TNF) is implicated in the
initiation of neuropathic pain. In vitro, TNF activates
p38 mitogen-activated kinase. Accordingly, we investigated whether TNF
activates the p38 cascade in vivo to trigger pain
behavior after spinal nerve ligation (SNL). Treatment starting 2 d
before SNL with the TNF antagonist etanercept (1 mg, i.p., every third
day) attenuated mechanical allodynia. Treatment starting 1 or 7 d
after SNL was ineffective. Similarly, intrathecal infusion of a p38
inhibitor (SB203580, 4 mg/d) was effective only if it was
started before but not 7 d after SNL. For both treatments, the
cessation of therapy resulted in increased allodynia. In separate
experiments using Western blots and immunohistochemistry, ipsilateral
lumbar spinal cord and L5 and L6 DRG were analyzed for total and
phosphorylated p38 after SNL alone or SNL combined with etanercept
pretreatment. In DRG, activated p38 was transiently elevated 5 hr after
SNL and returned to baseline by 1 d after SNL. Phosphorylated p38 was localized in small TNF-positive DRG neurons. In spinal cord, p38
was activated between 5 hr and 3 d after SNL and returned to
baseline within 5 d. In DRG, but not spinal cord, etanercept pretreatment blocked p38 activation. These data indicate that after SNL
treatment, phosphorylated p38 levels in spinal cord and DRG are
transiently elevated. In DRG, p38 activation is blocked by systemic TNF
inhibition. Parallel inhibition of p38 activation and allodynia may
represent a clinically relevant therapeutic window. These data suggest
a sequential role for TNF and p38 in the induction of neuropathic pain.
Key words:
cytokines; tumor necrosis factor-; dorsal root
ganglion; spinal nerve ligation; p38 MAPK; neuropathic pain
Copyright © 2003 Society for Neuroscience 0270-6474/03/2372517-05$05.00/0
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